Calcific Aortic Valve Disease (CAVD) occurs in >2% of the population over 65 years of age and often leads to valvular stenosis that necessitates valve replacement. CAVD is a progressive disease, but the specific molecular mechanisms of CAVD progression are not well defined, and inhibitors of CAVD progression have not been identified. Presently, there are no pharmacologic-based treatments for CAVD, and new therapeutic approaches for CAVD are needed. CAVD often occurs in the context of congenital malformation or comorbidities, such as atherosclerosis and kidney disease. However, it is not known if specific pathogenic mechanisms occur with CAVD of distinct etiologies. Studies of human explanted valves have implicated BMP, Notch, and Wnt signaling pathways in CAVD progression, and these pathways also have critical functions in heart valve and bone development. However, the specific contributions of these pathways to CAVD and the relationships among them have not been determined. We hypothesize that BMP and Wnt signaling act together to promote CAVD progression and that inhibition of BMP/pSmad1/5/8 signaling will prevent or inhibit CAVD progression in vivo. The proposed manipulations of specific signaling pathways in cultured valve interstitial cells, analyses of human explanted diseased aortic valves, and therapeutic intervention in a mouse model of CAVD will be used to identify target signaling pathways and test therapeutic strategies in CAVD progression. The aims are: 1) Determine the intersection of BMP and Wnt signaling pathways in osteogenic gene induction in mouse aortic valve interstitial cells. 2) Determine if BMP and Wnt pathway activation is predictive of calcific disease progression in human CAVD with distinct comorbidities. 3) Determine if inhibition of BMP signaling prevents or inhibits calciic disease progression in the Klotho-null model of CAVD. The goals of this study are to define critical signaling pathways that regulate CAVD progression and to identify pharmacologic inhibitors of valve calcification that are effective treatments for CAVD. (End of Abstract)